PXD038007-1

PXD038007 is an original dataset announced via ProteomeXchange.

Title	Toxicoproteomics reveals an effect of Clozapine on autophagy in human liver spheroids
Description	Clozapine is an atypical antipsychotic drug used to treat treatment-resistant schizophrenia. Its side effects, including liver enzyme abnormalities, experienced by many patients preclude its more common use as a first-line therapy for schizophrenia. Toxicoproteomic approaches have been demonstrated to effectively guide the identification of toxicological mechanisms. Here, to further our understanding of the molecular effects of clozapine, we performed a data-independent acquisition (DIA)-based quantitative proteomics investigation of clozapine-treated human liver spheroid cultures. In total, we quantified 4,479 proteins across the five treatment groups (vehicle; 15 µM, 30 µM, and 60 µM clozapine; and 10 ng/mL TNFα + IL-1β). Clozapine (60 µM) treatment yielded 36 differentially expressed proteins (FDR < 0.05). Gene-set enrichment analysis indicated perturbation of several gene sets, including interferon gamma signaling (e.g., interferon gamma receptor 1) and prominent autophagy-related processes (e.g., upregulation of sequestosome-1 (SQSTM1), MAP1LC3B/LC3B2, GABARAPL2, and nuclear receptor coactivator 4). The effects of clozapine on autophagy were confirmed by targeted mass spectrometry and western blotting using conventional SQSTM1 and LC3B markers. Combined with prior literature, our work suggests a broad contribution of autophagy to both the therapeutic and side effects of clozapine. Overall, this study demonstrates how proteomics can contribute to the elucidation of physiological and toxicological mechanisms of drugs.
HostingRepository	PRIDE
AnnounceDate	2022-12-13
AnnouncementXML	Submission_2022-12-13_00:48:04.979.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	catherineNury
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2022-11-07 09:54:44	ID requested
⏵ 1	2022-12-13 00:48:05	announced
2	2024-10-22 05:41:25	announced	2024-10-22: Updated project metadata.

Dataset with its publication pending

submitter keyword: Drug-induced liver injury

Data-independent acquisition

Clozapine

Proteomics

Systems toxicology

BjoernTitz
contact affiliation	PMI R&D, Philip Morris Products S.A., Quai Jeanrenaud 5, CH-2000 Neuchâtel, Switzerland
contact email	bjorn.titz@pmi.com
lab head
catherineNury
contact affiliation	Philip Morris International
contact email	catherine.nury@pmi.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD038007
     1. Label: PRIDE project
     2. Name: Toxicoproteomics reveals an effect of Clozapine on autophagy in human liver spheroids